Development of a practical Buchwald-Hartwig amine arylation protocol using a conveniently prepared (NHC)Pd(R-allyl)Cl catalyst

Article abstract of DOI:10.1039/b801479e

Continuing efforts to establish a more general "user-friendly" protocol for the palladium-catalysed arylation of amines (Buchwald-Hartwig reaction) are described herein. Significant advances have been made through the use of the versatile (SIPr)Pd(methallyl)Cl complex in conjunction with the reliable base lithium hexamethyldisilazide (LHMDS). The Royal Society of Chemistry.

Full text of DOI:10.1039/b801479e

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Development of a practical Buchwald–Hartwig amine arylation protocol using
a conveniently prepared (NHC)Pd(R-allyl)Cl catalyst†
Mark J. Cawley,a F. Geoffrey N. Cloke,b Richard J. Fitzmaurice,a Stuart E. Pearson,c James S. Scottc and
Stephen Caddick*a
Received 28th January 2008, Accepted 22nd April 2008
First published as an Advance Article on the web 6th June 2008
DOI: 10.1039/b801479e
Continuing efforts to establish a more general “user-friendly” protocol for the palladium-catalysed
arylation of amines (Buchwald–Hartwig reaction) are described herein. Significant advances have been
made through the use of the versatile (SIPr)Pd(methallyl)Cl complex in conjunction with the reliable
base lithium hexamethyldisilazide (LHMDS).
in amine arylation, Suzuki coupling and ketone arylation.7–10
Introduction
Their activity appears to stem from the fact that they offer more
In recent years, substantial research has been carried out on
facile access to the mono-ligated species than previously reported
protocols using imidazolium salts.11
N-heterocyclic carbene (NHC) ligands, and the successful re-
placement of phosphines by NHC ligands has had some notable
success in the development of catalysts for palladium chemistry.1,2
The Buchwald–Hartwig reaction is of considerable importance
in modern synthetic chemistry due to the regular occurrence of
the aniline moiety in a number of biologically active molecules
and dyestuffs.2,3 Whilst a plethora of Pd-NHC protocols have
been developed for this reaction, many are conducted using an
inert atmosphere and are often carried out using a glovebox,
significantly limiting the broader application of these techniques.
Furthermore, many of the studies published have emphasised the
range of halides, as opposed to diversity of amines, that undergo
the coupling reaction. For these reasons, continuing efforts are
being made within our group towards the development of an
idealised practical protocol which is efficient at room temperature
and can be applied generically across a wide range of amines and
halides. We now present a new study on amine arylation using a
new isolated Pd-NHC complex, which provides an improvement
on our previous reported protocols.4,5
As (NHC)Pd(R-allyl)Cl catalysts are isolated complexes, there
is good control over the Pd:ligand ratio (optimally 1:1).11,12
Additionally, these complexes can be made without a glovebox or
even the need for dry solvents.13,14 Work by Sigman has even shown
that complexes of this type are stable enough to be purified via flash
column chromatography on silica gel and that once prepared are
indefinitely air- and moisture-stable.13
Nolan and co-workers have recently demonstrated that terminal
substitution of the allyl scaffold in (NHC)Pd(allyl)Cl complexes
results in more facile activation of the complex to afford the active
species.11 This substitution stabilises the complex by increasing
the steric bulk about the Pd centre and by reducing the Pd–allyl
electron back-bonding. It is postulated that this results in a length-
ening of the Pd–C bond, hence making decomplexation of the
allyl ligand more facile. Having shown improvements using crotyl
and prenyl scaffolds, Nolan settled upon (NHC)Pd(cinnamyl)Cl
complexes as those affording the highest activity in Buchwald–
Hartwig and Suzuki couplings.11
Complexes of the type (NHC)Pd(R-allyl)Cl were first reported
by Caddick and Cloke in 2000 when (It-Bu)Pd(methallyl)Cl was
prepared while attempting the synthesis of the corresponding
biscarbene complex Pd(It-Bu)2 (Scheme 1).6 (NHC)Pd(R-allyl)Cl
complexes have since been elegantly shown to be very active
Despite the remarkable developments associated with the
(NHC)Pd(R-allyl)Cl class of catalyst, there are still opportunities
for further developments. One of the key issues for any amine
arylation protocol of this type is to develop a method which
will be applicable to a wide range of the approximately 80 000
commercially available compounds containing an N–H moiety,
and this has provided an impetus for further studies.15 In this paper
we present the results of our own study on the application of a new
variant of (NHC)Pd(R-allyl)Cl catalysts and their application to
aryl amination.
Scheme 1 First example of an (NHC)Pd(R-allyl)Cl complex.
Results and discussion
Catalyst preparation
aDepartment of Chemistry, University College London, London, WC1H 0AJ,
UK. E-mail: s.caddick@ucl.ac.uk
Although (It-Bu)Pd(methallyl)Cl had been prepared in an earlier
study, subsequent research has shown that the preferred NHC
ligand for amine arylation in most cases is SIPr (N,Nꢀ-bis(2,6-
diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene).4,6 Therefore,
(SIPr)Pd(methallyl)Cl 1 was selected for examination, as prior
bDepartment of Chemistry and Biochemistry, University of Sussex, Brighton,
BN1 9QJ, UK
cAstraZeneca, Alderley Park, Mereside, Cheshire, SK10 4TG, UK
† Electronic supplementary information (ESI) available: Additional exper-
imental information. See DOI: 10.1039/b801479e
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studies had not specifically evaluated the effect of non-terminal
allyl substitution. (SIPr)Pd(allyl)Cl 2 was also prepared for the
purposes of comparison.9,14
1 mol% of 1 leading to complete conversion within thirty minutes
(Table 1, entry 5). Further investigation revealed that the bulk
of the amination occurred in the first ten minutes, and that when
using 3 mol% of (SIPr)Pd(methallyl)Cl, the reaction was complete
within one minute in excellent yield (Table 1, entry 8).11
It was clear that (SIPr)Pd(methallyl)Cl had more potential use
as the catalyst in a general protocol than our previously described
in situ imidazolium salt method.5 It should also be noted that
although reactions were not possible using (SIPr)Pd(allyl)Cl and
the alkoxide base, this catalyst was shown to be more active with
LHMDS as base (Table 1, entry 9).
Despite the high yield obtained using 1 and LHMDS, the role of
the solvent was investigated further. As one of the key mechanistic
steps in the catalytic cycle is thought to be deprotonation of the
transmetalation complex,12 investigation was undertaken into how
solvents might affect this step and hence the reaction overall.
Accordingly, arylation of morpholine was performed in several
different aprotic solvents of varying dielectric constant (Table 2).
Only 1 mol% of 1 was employed to ensure that differences in
reactivity would be more noticeable. 1,4-Dioxane was found to
afford faster coupling than THF, albeit in a slightly reduced yield.
The use of toluene gave an increase in reaction time and a reduction
in yield compared to THF and 1,4-dioxane, but a moderate
yield was obtained nonetheless. DME has been reported to be
the preferred solvent for this reaction when used in conjunction
with KOt-Bu.11 However, it was found to not be suitable for this
protocol, affording only a low yield which was also observed with
diethyl ether. The reaction in DMF only afforded 17% of the
aniline product; no coupling product was obtained in DMA. This
appeared to show that highly polar solvents are not suitable in this
reaction, which was in agreement with a previous study by Kiil.16
The availability of commercial THF solutions of LHMDS also
made this a convenient and practical choice for further studies.
These procedures consisted of in situ formation of the NHC
through deprotonation of SIPr·HCl using KOt-Bu at 80 ◦C. This
was followed by addition of the relevant [Pd(R-allyl)Cl]2 complex
and stirring at room temperature to afford the catalyst (Scheme 2).
In the case of 2 it was possible to follow the literature procedure
closely, as this gave a pure sample of the complex (as confirmed
by elemental and spectroscopic analysis) in a yield of 66% (cf.
literature yield of 82%).14 However, in the case of catalyst 1 it was
only possible to obtain a pure sample of the complex via column
chromatography on silica gel (58% yield).13 This illustrates the
potential practicality of (NHC)Pd(R-allyl)Cl complexes, which
are not only highly active (vide infra), but are also tolerant of
routine manipulations generally carried out in organic chemistry
laboratories.
Scheme 2 Preparation of (SIPr)Pd(R-allyl)Cl complexes.
Optimisation of Buchwald–Hartwig amine arylation
With the above complexes prepared, an investigation into the
Buchwald–Hartwig reaction was undertaken. Optimisation was
undertaken using the pre-catalyst 1 with the aim of achieving yields
and reaction times comparable to or better than those afforded
by other protocols.11 Two simple substrates, 2-bromotoluene and
morpholine, were chosen for this study. Firstly, it was found that
when used as purchased, KOt-Bu was ineffective as a base in DME
with both 1 and 2 (Table 1, entries 1–2), but that a low yield of
the aniline could be obtained in THF with 1 (Table 1, entry 3).
This result could not be improved upon through the use of a
commercial 1 M solution of KOt-Bu in THF (Table 1, entry 4).
As with our previous imidazolium salt protocol, LHMDS was
shown to be fundamental to the success of amine arylation, with
Arylation of morpholine
Morpholine is a highly reactive substrate in amine arylation due
to its cyclic structure.17 Thus, with optimisation complete, the
arylation of morpholine was studied first. As with the previous
study, the reaction of 4-bromotoluene and morpholine was shown
to be a particularly facile reaction, with the reaction complete
in near quantitative yield within a minute at room temperature
(Table 3, entry 2). p-Tolyl triflate was found to react as quickly
as 4-bromotoluene.18 However, the yield with the aryl triflate was
slightly lower at only 70% (Table 3, entry 3), meaning that further
investigation and optimisation may be required.19
Table 1 Buchwald–Hartwig reaction of 2-bromotoluene and morpholine
using (SIPr)Pd(R-allyl)Cl catalysisa
Table 2 Effect of solvent in the Buchwald–Hartwig reaction of 4-
bromotoluene and morpholine using catalyst 1a
Entry
Catalyst
Base
Solvent
Time
Yield (%)
Entry
Solvent
er
2.21
2.38
4.34
7.20
7.52
Time/min
Yield (%)
1
2
3
4b
5
6
7
8
9
1 mol% 1
1 mol% 2
1 mol% 1
1 mol% 1
1 mol% 1
1 mol% 1
2 mol% 1
3 mol% 1
3 mol% 2
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
DME
DME
THF
THF
THF
THF
THF
THF
THF
24 h
24 h
6 h
6 h
30 min
10 min
2 min
1 min
2 min
—
—
<5
<5
95
82
93
99
89
1
2
3
4
5
6
7
1,4-Dioxane
Toluene
Et2O
DME
THF
DMF
DMA
10
60
30
45
20
30
30
89
65
50
38
97
17
—
36.7
37.8
a Reagents and conditions: 4-bromotoluene (1.0 mmol), amine (1.2 mmol),
base (1.1 mmol), and rt. b KOt-Bu administered as 1 M solution in THF.
a Reagents and conditions: halide (1.0 mmol), morpholine (1.2 mmol), 1
(1 mol%), LHMDS (1.1 mmol), solvent (1.1 mL), rt.
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Table 3 Buchwald–Hartwig reactions of aryl halides and morpholine using catalyst 1a
Entry
1
Halide
Product
Timeb/min
1
Yielda (%)
99
2
3
4
5
6
1
98
70
91
90
94
1
5
5
25
7
8
9
5
95
10
49
60 (10)
24 (52)
a Reagents and conditions: halide (1.0 mmol), amine (1.2 mmol), 1 (3 mol%), LHMDS (1.1 mmol, 1 M in THF), rt. b Values in parentheses refer to
reactions performed at 70 ◦C.‡
The presence of para-electron-donating groups did not sig-
nificantly hinder coupling with morpholine (Table 3, entries 4–
5).20 In fact, the exotherm that could be felt on the reaction
vessel at the start of the reaction11 was most obvious in the case
of 4-tert-butylbromobenzene. The reaction of 2-chlorotoluene
was also high yielding and rapid (Table 3, entry 6). This was
an interesting result, as our previous imidazolium salt method
required several days to successfully mediate the room temperature
coupling of aryl chlorides and then only in moderate yields.5 The
reaction was even faster with the less hindered 4-chlorotoluene
(Table 2, entry 7). However, the more electron-donating 4-
chloroanisole afforded only 49% of the desired aniline (Table 2,
entry 8).20 The highly hindered 2,6-dimethylchlorobenzene yielded
only 24% of the desired aniline. However, the yield was raised
to 52% by performing the reaction at 70 ◦C rather than room
temperature (Table 3, entry 9).‡
(Table 4). Having tested a range of halides, the decision was
then taken to keep the aryl halide component constant in
several reactions and to evaluate the effect of amine variation. 4-
Bromotoluene was selected for this role due to it being unhindered
and relatively electronically neutral.
High yields were obtained with several secondary cyclic amines.
Interestingly, thiamorpholine was shown to couple with a reduced
yield of 60% (Table 4, entry 7; cf. morpholine (Table 3, entry 2)).
This was nonetheless an important result, as it showed that the
(SIPr)Pd(methallyl)Cl precatalyst would enable the reactions of
sulfur-containing reagents, which have been reported to poison
palladium catalysts.20 Performing the coupling at 70 ◦C was found
to enhance the reactions of less reactive substrates, particularly
with secondary acyclic amines. It was also successfully demon-
strated that heteroaryl halides would react under this protocol: 2-
bromopyridine was coupled with piperidine in a high yield within
1 minute at room temperature, indicating that the lone pair of the
nitrogen on the pyridyl ring was not detrimental to the reactivity of
the Pd-NHC complex (Table 4, entry 20).§ Further investigations
are now underway with additional heteroaryl halides.
Scope of secondary alkyl amine
With investigations into the aryl halide component complete,
further studies to examine the scope of amines were initiated
Not all reactions of secondary alkyl amines were successful.
The hindered N-methyl-tert-butylamine, N-(tetrahydropyran-4-
yl)methylamine and cis-2,6-dimethylpiperidine all failed to react,
‡ In reactions quoted as being carried out at 70 ◦C, the hot plate for the
oil bath was set at 70 ◦C with only the bottom of the Schlenk tube placed
in the oil. In these reactions, no bubbling of the solvent was observed,
suggesting either that its boiling point was slightly elevated by the solutes
or rather that the actual temperature in the tube was no higher than 65 ◦C.
§ This reaction failed when repeated at room temperature without
(SIPr)Pd(methallyl)Cl with stirring for 6 hours.
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Table 4 Buchwald–Hartwig reactions of aryl halides with other secondary amines using 1a
Entry
1
Halide
Product
Timeb
Yieldb (%)
82
20 min
2
3
4
5
6
20 min
93
15 min
43
5 min
85
5 min (2 min)
30 min
40c (84)
65
7
8
10 min
5 min
60
96
9
10
11
5 min
80
5 min
96
16 h (3 h)
—c (9)c
12
5 min
83
13
14
15
16
17
18
19
18 h (5 h)
38c (85)
42c (86)
— (98)
— (82)
(10)
18 h (60 min)
24 h (60 min)
24 h (60 min)
(30 min)
(30 min)
(25)
24 h (90 min)
— (21)
20
1 min
91
a Reagents and conditions: halide (1.0 mmol), amine (1.2 mmol), 1 (3 mol%), LHMDS (1.1 mmol, 1 M in THF), rt. b Values in parentheses refer to
reactions performed at 70 ◦C.‡ c Reaction did not reach completion.
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either at room temperature or at 70 ◦C. It may be that they were
too sterically hindered for the N–H moiety to be able to access the
palladium centre in the transmetalation step.12
Higher catalyst loading was shown to promote the room
temperature couplings of the deactivated 4-chloroanisole and
the highly bulky 2,6-dimethylchlorobenzene with morpholine
(Scheme 3). This also enhanced the yield when mediating the
reaction of 2-bromotoluene and di-n-butylamine.
Arylation of primary amines
With a range of secondary amines studied, evaluation of the
reactivity of primary amines was undertaken. In the reaction of
4-bromotoluene with four equivalents of n-hexylamine, the halide
◦
was consumed within one hour in THF at 70 C, affording 64%
yield of the desired product. As in the previous study, heating
was deemed to be necessary with primary amines. However,
bisarylation was still observed, albeit in only 12% yield (Table 5,
entry 1).
Under the same conditions, the reactions of 4-bromotoluene
with benzylamine and (R)-(+)-1-phenylethylamine proceeded se-
lectively, with no bisarylation being observed (Table 5, entries
2–3). The selectivity here might be attributable to the greater steric
bulk of these amines.11,21 However, greater steric bulk also proved
problematic, since tert-butylamine and adamantylamine failed to
react. In the case of tert-butylamine (bp 46 ◦C), arylation also
failed to occur at 40 ◦C or at higher temperatures.
Scheme 3 Yield enhancement of through increased catalyst loading.
The sulfur-containing amine 2-(methylthio)ethylamine was
found to undergo arylation, but only afforded 14% yield of the
desired product (Table 5, entry 4). Nonetheless, this is promising,
showing that it might be possible to develop an amine arylation
protocol with these types of sulfur-containing substrates.
Conclusions
Although a general protocol has not yet been developed, the
present study has provided significant advances in the Buchwald–
Hartwig reaction. With suitable catalyst loading and/or heating,
(SIPr)Pd(methallyl)Cl and LHMDS effects the coupling of a
wide range of aryl halides with primary and secondary alkyl
amines; however, difficulties may be encountered when using bulky
substrates.
Studies will now concentrate on attempts at extending the
scope of amines that will undergo arylation in the presence of
(SIPr)Pd(methallyl)Cl.
Catalyst loading
In the optimisation process, the benefits of higher catalytic
loading were illustrated through higher yields and decreasing
reaction times. Although 3 mol% (SIPr)Pd(methallyl)Cl has been
shown to afford high yields with the more reactive substrates such
as morpholine and para-substituted aryl bromides, when dealing
with highly bulky substrates or deactivated aryl chlorides it was
not sufficient to mediate very efficient coupling. It appears here
that hydrodehalogenation may be the preferred reaction instead.
In such cases, a remedy may be to use higher catalyst loading.11,20,22
Experimental
(SIPr)Pd(methallyl)Cl 1
A two-necked flask with a magnetic stirrer was charged with
SIPr·HCl (1.9 g, 4.2 mmol) and potassium tert-butoxide (0.4 g,
3.6 mmol). A septum was placed on one neck and the remaining
neck was attached to a nitrogen line, after which the flask was
cycled with nitrogen and vacuum three times. Under a positive flow
of nitrogen, technical grade isopropanol (35 mL) was added via
syringe through the septum and the mixture was stirred for 2 h at
80 ◦C. After cooling to room temperature over 45 min, the septum
was removed, [Pd(methallyl)Cl]2 (0.55 g, 1.5 mmol) was added
quickly and the septum was replaced. The mixture was stirred for
2 h at room temperature, over which time its colour gradually
turned grey. It was opened to the air and stirred for 15 min. Water
(100 mL) was added and a solid precipitated. The water was
removed by filtration and the solid was taken up in chloroform
(100 mL). This solution was filtered through phase-separating
filter paper to remove the water and was concentrated in vacuo to
give a yellow oil. This crude residue was purified via flash column
chromatography (silica gel) using an eluent of diethyl ether–
petroleum spirit (3 : 2) to afford the title compound as an off-white
crystalline solid (1.02 g, 2.17 mmol, 72%, decomposes at 155 ◦C).
Table 5 Buchwald–Hartwig reactions of 4-bromotoluene and primary
amines using catalyst 1a
Yield (%)
Entry
1
Product
Time/min
60
Mono
64
Bis
12
2
3
30
30
45
70
—
—
4
60
14
—
a Reagents and conditions: 4-bromotoluene (1.0 mmol), amine (4.0 mmol),
1 (3 mol%), LHMDS (1.1 mmol, 1 M in THF), 70 ◦C.‡
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1H NMR (300 MHz, CDCl3): d 1.12 (s, 3H, CH2CMeCH2), 1.22 (d,
J = 6.9 Hz, 6H, CHMe2), 1.29 (d, J = 6.9 Hz, 6H, CHMe2), 1.34
(d, J = 6.9 Hz, 6H, CHMe2), 1.50 (d, J = 6.7 Hz, 6H, CHMe2), 1.56
(s, 1H, CH2CMeCH2), 1.75 (s, 1H, CH2CMeCH2), 2.68 (d, J =
3.6 Hz, 1H, CH2CMeCH2), 3.33–3.57 (m, 4H, CHMe2), 3.69 (d,
J = 3.1 Hz, 1H, CH2CMeCH2), 3.97–4.08 (m, 4H, NCH2), 7.25–
7.19 (m, 4H, Ar), 7.34 (t, J = 7.7 Hz, 2H, Ar). 13C NMR (75 MHz,
CDCl3): d 22.4, 23.7, 23.8, 26.6, 26.7, 28.4, 28.6, 49.5, 53.8, 72.2,
124.3, 124.4, 129.0, 129.7, 136.6, 147.1, 147.3. C.I. MS (relative
intensity): 550 (10), 496 (50), 389 (10), 347 (10), 188 (15), 146 (13),
91 (31). HRMS C.I. [M+], Calcd.: 587.23841. Actual: 587.23643.
Anal. Calcd.: C 63.37, H 7.72, N 4.77. Actual: C 63.41, H 7.80,
N 4.65. IR (KBr, cm−1) 2962, 2925, 2868, 1448, 1425, 1382, 1363,
1326, 1267, 1240, 1055, 837, 802, 758, 731, 700, 621.
gratitude is also extended to James Mok for his assistance in
this study. We also gratefully acknowledge BBSRC, Wellcome
Trust, CEM UK and GSK for support of our programme. We
acknowledge the provision of mass spectra from the EPSRC Mass
Spectrometry Service at Swansea.
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General procedure for amine arylation
An oven-dried Schlenk tube was charged with an aryl halide
(1.0 mmol), an amine (1.2 mmol, 1.2 eq.), (SIPr)Pd(methallyl)Cl
(18 mg, 0.03 mmol, 3.0 mol%) and a magnetic stirrer bar, and
sealed with a septum. The flask was evacuated and backfilled with
inert gas three times, after which LHMDS (1.1 mL of 1M solution
in THF, 1.1 mmol, 1.1 eq.) was added via syringe. The mixture
was stirred until the aryl halide had been consumed, as judged by
TLC. It was diluted with ethyl acetate and filtered through a short
plug of silica. The solvent was removed in vacuo and the crude
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1
compound within 10 min as a white solid (mp 40 C). H NMR
(300 MHz, CDCl3): d 2.29 (s, 3H, ArCH3), 2.75–2.79 (m, 4H,
SCH2), 3.46–3.49 (m, 4H, NCH2), 6.85 (d, J = 8.8 Hz, 2H, Ar),
7.08 (d, J = 8.8 Hz, 2H, Ar). 13C NMR (75 MHz, CDCl3): d 20.5,
27.2, 52.8, 117.7, 129.6, 129.8, 149.6. E.I. MS (relative intensity):
193 (M+, 54), 119 (100). HRMS E.I. [M+], Calcd.: 193.09197.
Actual: 193.09170. IR (KBr, cm−1): 2954, 2908, 2873, 2827, 2754,
1616, 1573, 1514, 1450, 1415, 1336, 1290, 1224, 1193, 1168, 1136,
1029, 970, 893, 819, 530.
19 J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046–2067.
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Acknowledgements
We wish to gratefully acknowledge the financial support of
AstraZeneca and EPSRC in this programme of research. Sincere
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2820–2825 | 2825
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